Measurement Error in Diet and Physical Activity Epidemiology. Ross Prentice, October 22, 2015

Transcription

1 Mesurement Error in Diet nd Physicl Activity Epidemiology Ross Prentice, October 22, 2015

2 Design of WHI CT=68,132 DM 48,835 WHI =161,808 HRT 27,347 CD 36,282 os 93,676

3 History: WHI Development nd Reserch Progrm Phses Pre-WHI ( ) NCI-sponsored Women s Helth Tril pilot nd fesibilities tril towrd full-scle tril of low-ft diet intervention for brest cncer prevention Observtionl studies of postmenopusl estrogens (e.g., Premrin) nd estrogens plus progestin (e.g., Prempro) by epidemiologic nd clinicl communities; NHLBI-sponsored intermedite outcomes tril- PEPI

4 WHI nnounced by NIH Director Bernedine Hely (1992) s trns-nih inititive. Contrct for Clinicl Coordinting Center (CCC) in 1992 nd for the initil 16 of 40 Clinicl Centers in 1993 IOM Review in 1994 WHI llowed to proceed; progrm office moved to NHLBI

5 Women s Helth Inititive Clinicl Centers Fred Hutchinson Cncer Reserch Center Univ. of Minnesot Med. Ctr. Medicl College of Wisconsin Kiser Foundtion Reserch Institute Univ. of Wisconsin Univ. of Iow Univ. of Mss Med. Ctr. Albert Einstein Brighm & Women s Hosp. Col. of Med. Mem. Hosp. of Rhode Is. Univ. of Pittsburgh SUNY, Stony Brook Wyne Stte Univ. Rush-Presb. Northwestern Univ. St. Luke s Ohio Stte Univ. Med. Ctr. Univ. of Cliforni, Dvis Univ. of Nevd, Reno Kiser Foundtion Reserch Institute Lelnd Stnford Junior University Univ. of Med. & Dent. of New Jersey Medlntic Res. Inst./Howrd Univ. Univ. of Cincinnti Medicl Center Univ. of Cliforni, Los Angeles George Wshington Univ. Wke Forest University Univ. of Cliforni, Irvine { SUNY Bufflo Univ. of Tennessee Hrbor-UCLA Reserch & Eduction Inst. Univ. of North Crolin Emory Univ. Sch. of Medicine Univ. of Cliforni, Sn Diego Univ. of Albm Univ. of Arizon t Tucson Univ. of Texs Helth Science Ctr., Sn Antonio Bylor College of Medicine Univ. of Florid Univ. of Mimi Univ. of Hwii

6 Intervention Phse ( ) Recruitment, protocol nd procedures, intervention implementtion Dt nd specimen collection; qulity ssurnce; dt nd sfety monitoring Complex orgniztion nd committee structure(s)

7 Intervention Phse ( ) E+P tril stopped erly (2002) E-lone tril stopped erly (2004) DM nd CD interventions concluded t plnned termintion (2005)

8 Postmenopusl Hormone Therpy YES Conjugted equine estrogen (CEE) mg/d N= 10,739 Plcebo Hysterectomy NO N= 16,608 CEE mg/d + medroxyprogesterone cette (MPA) 2.5 mg/d Plcebo

9 Clinicl Outcomes in the WHI Postmenopusl Hormone Therpy Trils (WHI Study Group, JAMA 2002; Anderson et l, JAMA 2004) Outcomes Coronry hert disese Stroke Venous thromboembolism Invsive brest cncer Colorectl cncer Endometril cncer Hip frcture Deth due to other cuses Globl index Number of women Follow-up time, men (SD), mo E+P Tril Hzrd Rtio 95% CI E-Alone Tril Hzrd Rtio 95% CI (16.1) (15.0) (19.3) (19.7)

10 Qurterly Incidence of Brest Cncer in Women between the Ages of 50 nd 69 Yers, According to Estrogen Receptor (ER) Sttus ( ) Dt re from the NCI s SEER registries. (Rvdin et l, NEJM, 2007)

11 Low Ft Dietry Pttern Support from interntionl correltion nlyses, rodent feeding studies; nd cse-control studies concerning dietry ft nd brest cncer, but cohort studies were generlly unsupportive

12 Low Ft Dietry Pttern Tril: Findings nd Methodology Intervention Group Gols: 20% energy from ft 5 or more fruit nd vegetble servings dily 6 or more grin servings dily Photos courtesy of USDA Agriculturl Reserch Service

13 Men (SD) of Nutrient Consumption by Rndomiztion Group Yer 1 Yer 1 Yer 3 Yer 6 Difference Difference Difference Intervention Control Ft (% of clories) 24.3 (7.5) 35.1 (6.9) 10.7* (7.0) 9.5* (7.4) 8.1* (7.8) Totl Ft (g) 40.8 (21.4) 63.0 (31.0) 22.4* (31.1) 20.1* (32.0) 18.4* (33.5) Energy (kcl) 1500 (544) 1593 (644) 95.8* (616.2) 92.5* (632.1) 119.9* (662.9) *Difference significnt t p<0.001 from two smple t-test

14 Comprison of Cncer Incidence Rtes between Intervention nd Comprison Groups in the Women s Helth Inititive (WHI) Dietry Modifiction Tril* Prentice et l (JAMA, 2006; JNCI, 2007); Beresford et l (JAMA, 2006) Incidence per 1000 person yers ( Number of cses) Cncer Site Intervention Comprison p HR(95% CI) Brest 4.15 (655) 4.52 (1072) (0.83 to 1.01) Colorectl 1.27 (201) 1.18 (279) (0.90 to 1.29) Ovry 0.36 (57) 0.43 (103) (0.60 to 1.14) Endometrium 0.79 (125) 0.71 (170) (0.88 to 1.40 All other sites 4.56 (720) 4.81 (1140) (0.86 to 1.04) Totl cncer (1687) (2661) (0.89 to 1.01) *Tril includes 19,541 women in the intervention group nd 29,294 women in the comprison group. Weighted log-rnk test (two-sided) strtified by ge (5-yer ctegories) nd rndomiztion sttus in the WHI hormone therpy tril. Weights increse linerly from zero t rndom ssignment to mximum of 1.0 t 10 yers. HR= hzrd rtio; CI =confidence intervl, from proportionl hzrds model strtified by ge (5-yer ctegories), nd rndomiztion sttus in the WHI hormone therpy tril.

15 Low-Ft Dietry Pttern Intervention Effects on Brest nd Ovrin Cncer, in Reltion to Bseline 4-Dy Food Record % of Energy from Ft % of Energy from Ft Men (SD) Difference Hzrd Rtio Interction (4DFR) Between Groups (95% CI) P-Vlue Brest Cncer (1727 cses) < (6.2) 0.97 (0.79, 1.20) (6.5) 1.08 (0.89, 1.30) (6.6) 0.85 (0.70, 1.03) (7.0) 0.78 (0.64, 0.95) 0.04 Ovry Cncer (160 cses) < (0.76, 2.33) (0.32, 1.12) (0.31, 1.08) 0.05

16 Some Observtions Chronic disese rtes tend to be highly disprte round the world, with mny disese rtes highly elevted in Western popultions. Migrnt popultions tend to ssume rtes tht previl in their new environment, within few genertions. Risk prediction models, including those incorporting findings from recent GWAS, do not llow one to identify persons who will develop specific disese, with even moderte precision. Impliction: There is still much to be lerned bout the determinnts of chronic disese risk, including identifiction of importnt modifible risk fctors.

17 Where to Look? Chnges in incidence rtes mong migrnts, nd time trends in incidence rtes, suggest tht chronic disese risk depends importntly on common/ordinry hbits nd exposures. Genetic/genomic fctors my lso be importntly involved in chronic disese pthogenesis, but perhps more often s meditors thn s primry exposures. Diet nd physicl ctivity ptterns continue s likely sources of disese rte vritions, but few cler ssocitions hve emerged to dte, especilly from nutritionl epidemiology.

18 Mesurement Error in Nutritionl Epidemiology Cohort studies hve provided the minsty epidemiologic pproch to nutritionl epidemiology in recent yers. These nd other observtionl study designs need to contend with the usul confounding nd outcome scertinment bis issues, but lso with mesurement issues in dietry ssessment, tht my be dominnt. Consider hzrd rte h(t;z,v) t cohort follow up time t, given bseline dietry vrible Z, nd other potentil risk fctors V. A Cox model specifies h(t;z,v)= h(t) exp(zb +V).

19 Mesurement Error (continued) Becuse of mesurement error, Z cn be ssessed only indirectly, by mens of vrible Q (e.g., n FFQ ssessment of Z). The hzrd function tht cn be estimted h(t ;Q,V) is typiclly (rre disese) well pproximted by h(t ;Q,V)= h* (t) exp {E(Z;Q,V)b+V}. Hence, to ddress mesurement error in ssessment of Z, one needs to ppropritely estimte E(Z;Q,V). Objective mrkers (W) dhering to clssicl mesurement model W=Z+u re crucil for such estimtion.

20 Regression Clibrtion A clssicl mesurement model entils W=Z+u with men zero noise u tht is independent of the trgeted Z, independent of ll pertinent study subject vribles V nd, importntly, independent of the mesurement error ssocited with the self report ssessment Q, in which cse E(W;Q,V)= E(Z;Q,V) And E(Z; Q,V) cn be estimted by regression of the biomrker W on the self report Q nd study subject chrcteristics V (confounders; fctors involved in systemtic bis in Q; or tht my help to explin the vrition in W, or Z, in the study popultion).

21 Nutrient nd Physicl Activity Biomrkers Studies in WHI 544 DM Tril women completed two-week DLW protocol with urine nd blood collection nd with FFQ nd other questionnire dt collection (50% intervention, 50% control). A 20% relibility subsmple repeted protocol bout 6 months lter. (NBS; ) Biomrker study mong 450 women in the WHI Observtionl Study for evluting nd compring mesurement properties of dietry nd physicl ctivity ssessment pproches (frequencies, records, nd reclls); with 20% relibility subsmple. (NPAAS; ) Recently completed feeding study mong 153 WHI women in Settle, for development of objective mrkers for dditionl nutrients or foods. (NPAAS II; 2010-present)

22 Nutrition nd Physicl Activity Biomrker Study Prticipnts (NBS nd NPAAS) Coordintion (FHCRC): Mrin Neuhouser, Lesley Tinker, Johnn Lmpe, Ross Prentice Clinicl Center PIs: Shirley Beresford - Settle Bette Cn - Oklnd Lind Vn Horn - Chicgo Cynthi Thomson - Arizon Ysmin Mossvr-Rhmni - NYC Kren Johnson - Memphis Glori Srto - Wisconsin Judy Ockene - U Mss Gerrdo Heiss - UNC Lewis Kuller* - Pittsburgh Mrci Stefnick* - Stnford Ellen Smit* - Portlnd Annlouise Assf* - Pwtucket *NBS only NPAAS only Additionl Key Collbortors: Dle Schoeller - Wisconsin (DLW); Sheil Binghm Cmbridge (UN); Xioling Song, Ying Hung, Chongzhi Di FHCRC; Cheng Zheng Milwukee; Pmel Shw - U Penn; Jennette Besley - Einstein; Dn Rftery University of Wshington

23 WHI Nutritionl Biomrkers Study Procedures (NBS nd NPAAS I) Invittion letter nd screening interview Not eligible Informed consent DLW dosing Schedule first visit 3 post-dlw spot urines Complete dietry, physicl ctivity, nd other questionnires 24-hr urine collection instructions 4-dy food record instructions Visit 1 Bring 24-hr urine Weight Fsting blood drw 2 spot urines Indirect clorimetry Physicl ctivity q 3 24HRs over next 23 months Visit 2 Subset, 20% Pre-DLW spot urine 2 weeks Anthropometry Collect 24-hr urine Eligible & willing Repet ll procedures 6 mo lter (relibility study)

24 Mesurement Model Wbiomrker = Z + e Qself-report = 0 + 1Z + 2V + ε Estimte disese odds rtios (Sugr, Wng nd Prentice 2007, Biometrics), or hzrd rtios (Shw nd Prentice, 2012, Biometrics), using Q from cohort nd W from sub-cohort

25 Clibrtion nd Hzrd Rtio Estimtion Under joint normlity ssumption for (Z, Ɛ) given V, the conditionl expecttion of Z is of the form E (Z Q,V) = b0 + b1q + b2v E(W I Q,V) = E (Z Q,V) nd Clibrted estimtes of Z from liner regression of W on (Q,V) in the biomrker subsmple Hzrd rtios estimtion by inserting clibrted consumption estimtes into Cox regression, nd using bootstrp procedure for stndrd error estimtion. Some importnt nunces if some elements of V (e.g., BMI) re not included in disese risk model (Prentice nd Hung, 2011, Cn J Stt; Zheng et l, 2014, AJE).

26 Clibrtion Eqution Coefficients (β), Stndrd Errors (SE), nd Percent of Biomrker Vrition Explined (R2) from Regression of Log(biomrker) on Log(self-report), nd Other Fctors mong 450 Observtionl Study Women Energy Vrible Food Frequency β SE R 2 4DFR 2 Adj R β SE 24HR R 2 2 Adj R β SE R 2 Adj R ENERGY Intercept FFQ 4DFR 24HR BMI Age Blck Hispnic Other minority b (Totl) Prentice et l (2011, AJE)

27 Clibrtion Eqution Coefficients (β), Stndrd Errors (SE), nd Percent of Biomrker Vrition Explined (R2) from Regression of Log(biomrker) on Log(self-report), nd Other Fctors mong 450 Observtionl Study Women Protein Vrible Food Frequency 4DFR 24HR β Intercept FFQ SE R2 Adj R β SE R2 Adj R Blck Hispnic Other Age R2 Adj R HR BMI SE DFR β minority (Totl) b Prentice et l (2011,AJE)

28 Other Regression Clibrtion Activities Using NBS/NPAAS I Dt Activity-Relted Energy Expenditure (AREE) Objective mesure: DLW totl energy expenditure minus resting energy expenditure from indirect clorimetry Self-report: AAFQ, 7dPAR, PHQ+ (Neuhouser et l, 2013, AJE) Sodium nd Potssium nd their Rtio Objective mesure: 24-hour urinry recovery Self-report: FFQ, 4DFR, 24HR for these nutrients (Hung et l, 2014, Hypertension) Totl Sugrs Objective mesure: 24-hour urinry recovery of fructose nd sucrose Self-report: FFQ, 4DFR, 24HR totl sugrs (Tsevsk et l, 2014, CEBP) Respirtory Quotient Objective mesure: RQ from indirect clorimetry Self-report: FQ = 0.7 (% energy from F+A) (% energy from protein) (% energy from crbohydrte) (Prentice et l, 2013, CEBP)

29 Regression clibrtion β-coefficients nd percent of biomrker vrition explined in the WHI NPAAS (Neuhouser et l, 2013, AJE) AAFQ PAR Adjusted Vrible β R2 R2 PHQ Adjusted β R2 R2 β R2 R2 Intercept 4.789* Log (self report AREE) 0.273* * * Age 0.018* * * Rce 5.353* Adjusted 5.632* Blck Hispnic 0.108* 0.141* BMI TOTAL 0.015* * * * Regression coefficient differs from zero t P<0.05 Adjusted R2 is corrected for biomrker mesurement error, i.e., R2/log(biomrker) correltion from relibility study

30 Estimted Hzrd Rtios (95% Confidence Intervls) for 20% Increments in Totl Energy (TE) Consumption nd in Activityrelted Energy Expenditure (AREE), With nd Without Clibrtion to Correct for Mesurement Error, for Vrious Crdiovsculr Disese Ctegories in the Women s Helth Inititive Observtionl Study (OS) from Bseline ( ) Through September 30, 2010 (Zheng et l, 2014, AJE) Unclibrted Energy Clibrted AREE Energy AREE Disese Ctegory HR 95% CI HR 95% CI HR 95% CI HR 95% CI Totl CHD , , , ,0.95 Nonftl MI , , , ,0.97 Coronry Deth , , , ,0.86 Congestive Hert Filure , , , ,0.79 CABG nd PCI , , , ,1.03 Totl Stroke , , , ,0.99 Ischemic Stroke , , , ,0.94 Hemorrhgic Stroke , , , ,2.20 Totl CVD: CHD nd Stroke , , , ,0.92 Totl CVD including CABG nd PCI , , , ,0.93

31 Estimted Hzrd Rtio (95% Confidence Intervl) for 20% Increments in Totl Energy (TE) Consumption nd in Activity-relted Energy Expenditure (AREE), With nd Without Clibrtion to Correct for Mesurement Error, for Vrious Cncer Ctegories, in the Women s Helth Inititive Observtionl Study (OS) from bseline ( ) Through September 30, 2010 (Zheng et l, 2014, AJE) Unclibrted Clibrted Cncer Ctegory Energy HR 95% CI AREE HR 95% CI Energy HR 95% CI HR Totl Invsive Cncer Obesity relted Cncer Brest Cncer Colon Cncer Rectum Cncer Ovry Cncer Endometril Cncer Bldder Cncer Kidney Cncer Pncres Cncer Lung Cncer Lymphom Leukemi , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,3.12 AREE 95% CI 0.73, , , , , , , , , , , , ,1.18

32 Estimted Hzrd Rtio (95% Confidence Intervl) for 20% Increments in Totl Energy (TE) Consumption nd in Activity-relted Energy Expenditure (AREE), With nd Without Clibrtion to Correct for Mesurement Error, for Dibetes Incidence, in the Women s Helth Inititive Observtionl Study (OS), from Bseline ( ) Through September 17, 2012 (Zheng et l, 2014, AJE) Unclibrted Energy Clibrted AREE Energy AREE Outcome Ctegory HR 95% CI HR 95% CI HR 95% CI HR 95% CI Dibetes Mellitus , , , ,0.83

33 Biomrker Development for Additionl Nutrients/Dietry Components Humn Feeding Study for Biomrker Development (NPAAS II) Provide ll food nd drink over two-week feeding period Use blood nd urine nutritionl mesures nd study subject chrcteristics to explin vrition in provided nutrient consumption Use highly individulized diet tht ims to pproximte usul diet so tht blood nd urine nutritionl mesures will stbilize quickly, nd to preserve nutrient consumption vrition in the study cohort Sttisticl model: W = c0 + c1x + c2v + e W is log-provided nutrient. X is comprised of log- urine or blood nutritionl mesures (including metbolomic profile ssessments - Rftery). V is vector of study subject chrcteristics. A potentilly useful biomrker should be highly correlted with W (e.g., correltion 50%), nd void importnt omissions to (X,V). Feeding study mong 153 WHI women in Settle completed in 2013.

34 Rftery Lb Pltforms Quntitted metbolites generted from the NPAAS Btch Method Specimen Metbolites Detected CV* 1 Trgeted LC MS/MS Serum 131 queous metbolites 7.9% 1 Globl LC QTOF MS Serum 494 lipids 6.7% 1 NMR Urine 48 metbolites 3.9% 1 Globl GC MS Urine 122 metbolites 15% 2 Trgeted LC MS/MS Serum 105 queous metbolites 8.0% 2 Globl LC QTOF MS Serum 231 lipids 15.7% 2 NMR 24hr Urine 53 metbolites 5.0% 2 NMR Spot Urine 53 metbolites 1.6% * Medin CV for blinded duplicte smples. Finl Btch 2 GCMS relibility dt still under development.

35 Correltions of Provided Intke with Metbolomic Profile Estimted Intkebetween for Severl Nutritionl Vribles NPAAS II Correltion* men dily provided (consumed) nutrient intke nd in corresponding metbolite bsed cross vlidted estimted intke for specific nutrition vribles.** Blood+24 hr urine Blood Only 24 hr urine only Nutritionl Vrible Energy, kcl Protein, g Nitrogen, g Ft, g Sturted ft, g Monounsturted ft, g IQR intke rnges Polyunsturted ft, g Linoleic cid,g Linolenic cid, g EPA, g DHA, g Crbohydrte, g Added sugrs, g Soluble fiber, g Insoluble fiber, g Alcohol, g Cffeine, mg 3 Methyhistidine, mg Vitmin C, mg Vitmin D, mcg Sodium, mg Potssium, mg Folte (nturl), mcg Btch 1 Btch 2 Btch 1 Btch 2 Blood +spot urine Spot urine only Btch 2 Btch 2 Btch 2 Btch *Tbulr entries re, more precisely, the squre roots of the % (log trnsformed) provided nutrient intke for the test smple explined by the pplying the trining smple metbolite model to estimte (log trnsformed) intke in the (20%) test smple. These R vlues my be slightly less thn the correltion between (log trnsformed) provided nd estimted intke since regression coefficients re not re estimted in ppliction to the test smple. **Btch 1 includes blood nd 24 hr urine for the first 50 women, nd Btch 2 includes these specimens for the subsequent 103 women, long with spot urine for ll 153 feeding study women

36 Summry/Additionl Comments The use of objective mesures in nutritionl nd physicl ctivity epidemiology provides prcticl mens of enhncing ssocition study relibility in these importnt reserch res. Additionl objective mesures forthcoming from ccelerometer dt for detiled physicl ctivity ptterns (Andre LCroix, OPACH); could lso consider using DXA dt in BMD sub-cohort for clibrted body composition.

37 Looking Ahed Metbolomic profiling using stored blood nd urine (trgeted MS, lipidomics; NMR) provides n pproch to identifying mny dditionl dietry biomrkers (including totl energy biomrkers from stored specimens). Novel biomrkers cn be pplied in regression clibrtion mode using self-report dt, or pplied directly to cse-control dt, bypssing ny use of dietry self-report dt (NPAAS III). Addressing exposure mesurement error is key to obtining relible informtion in these crucil public helth res.